Department of Physiological Sciences, Eastern Virginia Medical School, Norfolk, VA 23501, USA.
Endocrinology. 2024 May 27;165(7). doi: 10.1210/endocr/bqae071.
Follicular androgens are important for successful ovulation and fertilization. The classical nuclear androgen receptor (AR) is a transcription factor expressed in the cells of the ovarian follicle. Androgen actions can also occur via membrane androgen receptor SLC39A9. Studies in fish ovary demonstrated that androgens bind to SLC39A9 and increase intracellular zinc to regulate ovarian cell function. To determine if SLC39A9 is expressed and functional in the key cell types of the mammalian ovulatory follicle, adult female cynomolgus macaques underwent ovarian stimulation. Ovaries or ovarian follicular aspirates were harvested at 0, 12, 24, and 36 hours after human chorionic gonadotropin (hCG). SLC39A9 and AR mRNA and protein were present in granulosa, theca, and vascular endothelial cells across the entire 40-hour ovulatory window. Testosterone, bovine serum albumin-conjugated testosterone (BSA-T), and androstenedione stimulated zinc influx in granulosa, theca, and vascular endothelial cells. The SLC39A9-selective agonist (-)-epicatechin also stimulated zinc influx in vascular endothelial cells. Taken together, these data support the conclusion that SLC39A9 activation via androgen induces zinc influx in key ovarian cells. Testosterone, BSA-T, and androstenedione each increased proliferation in vascular endothelial cells, indicating the potential involvement of SLC39A9 in ovulatory angiogenesis. Vascular endothelial cell migration also increased after treatment with testosterone, but not after treatment with BSA-T or androstenedione, suggesting that androgens stimulate vascular endothelial cell migration through nuclear AR but not SLC39A9. The presence of SLC39A9 receptors and SLC39A9 activation by follicular androstenedione concentrations suggests that androgen activation of ovarian SLC39A9 may regulate ovulatory changes in the mammalian follicle.
卵泡雄激素对于成功排卵和受精至关重要。经典的核雄激素受体（AR）是在卵巢卵泡细胞中表达的转录因子。雄激素作用也可以通过膜雄激素受体 SLC39A9 发生。鱼类卵巢的研究表明，雄激素与 SLC39A9 结合并增加细胞内锌以调节卵巢细胞功能。为了确定 SLC39A9 是否在哺乳动物排卵卵泡的关键细胞类型中表达和发挥功能，成年雌性食蟹猴接受了卵巢刺激。在 hCG 后 0、12、24 和 36 小时收获卵巢或卵巢卵泡抽吸物。SLC39A9 和 AR mRNA 和蛋白存在于颗粒细胞、膜细胞和血管内皮细胞中，整个 40 小时排卵窗口均如此。睾酮、牛血清白蛋白结合的睾酮（BSA-T）和雄烯二酮刺激颗粒细胞、膜细胞和血管内皮细胞的锌内流。SLC39A9 选择性激动剂（-）-表儿茶素也刺激血管内皮细胞的锌内流。这些数据表明，SLC39A9 通过雄激素的激活诱导关键卵巢细胞中的锌内流。睾酮、BSA-T 和雄烯二酮均增加血管内皮细胞的增殖，表明 SLC39A9 可能参与排卵血管生成。用睾酮处理后血管内皮细胞迁移也增加，但用 BSA-T 或雄烯二酮处理后则没有，这表明雄激素通过核 AR 而非 SLC39A9 刺激血管内皮细胞迁移。卵泡雄激素存在 SLC39A9 受体和 SLC39A9 的激活表明，雄激素激活卵巢 SLC39A9 可能调节哺乳动物卵泡的排卵变化。
